It has been demonstrated that the T cell proliferative response to Con A and the T cell dependent antibody responses to the soluble antigens TNP-KLH, TNP-T,G-(A-L), and TNP-Nuclease require the participation of accessory cells. This subpopulation of spleen cells has been shown to be glass adherent radioresistant, non-T, non-B and to express Ia (I region associated) determinants encoded in I-A and I-E/C. In addition, cells within the splenic adherent cell population are the predominant stimulators of the one way murine mixed lymphocyte response when responder and stimulator cells differ either at H-2 or the Mls locus. These stimulator cells also bear I-A and I-E/C encoded determinants and their ability to stimulate allogeneic T cells could be inhibited with specific anti-Ia reagents.